PREVENTION AND TREATMENT OF CEREBRAL AMYLOID ANGIOPATHY

• US 20080292625A1
• Filed: 04/18/2008
• Published: 11/27/2008
• Est. Priority Date: 04/18/2007
• Status: Abandoned Application

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Wyeth LLC (Pfizer Inc.)
• Inventors: Games, Kate Dora, Schroeter, Sally
• Application Number:
  US12/106,206
• Publication Number:
  US 20080292625A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 against material from animals or humans

Abstract

The invention provides improved agents and methods for treatment of cerebral amyloid angiopathy (CAA) and methods to effect prophylaxis of CAA. The methods can treat CAA concurrently with Alzheimer'"'"'s disease or separately. The methods can effect prophylaxis of CAA concurrently with Alzheimer'"'"'s disease or separately. The methods involve administering antibody that is specific for the N-terminus of Aβ or an agent that can induce such an antibody.

Claims

1. A method of treating CAA, comprising

administering to a patient having or suspected of having CAA an effective regime of an agent, wherein the agent is antibody that is specific for the N-terminus of Aβ

or induces such an antibody after administration to the patient and thereby treating the patient.

2. The method of claim 1, wherein the agent is an antibody.

3. The method of claim 2, wherein the agent is an antibody that binds within residues 1-5 of Aβ

.

4. The method of claim 2, wherein the antibody is a humanized, human, or chimeric antibody.

5. The method of claim 4, wherein the antibody is humanized 3D6 or humanized 12A11.

6. The method of claim 5, wherein the 3D6 humanized antibody is bapineuzumab.

7. The method of claim 1, wherein the agent is a fragment of Aβ

.

8. The method of claim 7, wherein the fragment begins at residue 1 of Aβ

and ends at one of residues 5-10 of Aβ

.

9. The method of claim 7, wherein the fragment is Aβ

1-7.

10. The method of claim 7, wherein the fragment of Aβ

is administered with a pharmaceutically acceptable adjuvant.

11. The method of claim 7, wherein the fragment of Aβ

is linked to a carrier that helps the fragment induce antibodies to the fragment.

12. The method of claim 11, wherein the carrier is linked to the C-terminus of the fragment.

13. The method of claim 1, further comprising determining that a patient has CAA, wherein the determining step occurs before the administration step.

14. The method of claim 13, wherein the determining step determines that a patient is suffering from a clinical symptom of CAA.

15. The method of claim 1, wherein the patient lacks plaques characteristic of Alzheimer'"'"'s disease in the brain.

16. The method of claim 14, wherein the patient lacks symptoms of Alzheimer'"'"'s disease.

17. The method of claim 1, wherein the patient has had a heart attack or stroke.

18. The method of claim 1, wherein the dosage of the antibody is between about 0.01 to about 5 mg/kg.

19. The method of claim 1, wherein the dosage of the antibody is between about 0.1 to about 5 mg/kg.

20. The method of claim 18, wherein the dosage is about 0.5 mg/kg.

21. The method of claim 18, wherein the dosage is about 1.5 mg/kg.

22. The method of claim 18, wherein the dosage is between about 0.5 to about 3 mg/kg.

23. The method of claim 18, wherein the dosage is between about 0.5 to about 1.5 mg/kg.

24. The method of claim 18, wherein the dosage is administered on multiple occasions.

25. The method of claim 18, wherein the dosage is administered is weekly to quarterly.

26. The method of claim 18, wherein the dosage is administered every 13 weeks.

27. The method of claim 1, wherein the antibody is administered intravenously or subcutaneously.

28. The method of claim 1, further comprising monitoring for changes in signs or symptoms of CAA responsive to the administrating step.

29. The method of claim 1, further comprising administering a second agent effective to treat CAA.

69. The method of claim 2, wherein the antibody is administered in a regime sufficient to maintain an average serum concentration of the antibody in the patient in a range of 1-15 μ

g antibody/ml serum and thereby treating the patient.

70. The method of claim 69, wherein the average serum concentration is within a range of 1-10 μ

g antibody/ml serum.

71. The method of claim 70, wherein the average serum concentration is within a range of 1-5 μ

g antibody/ml serum.

72. The method of claim 71, wherein the average serum concentration is within a range of 2-4 μ

g antibody/ml serum.

73. The method of claim 69, wherein the antibody is administered intravenously.

74. The method of claim 73, wherein a dose of 0.5-1.0 mg/kg is administered monthly.

75. The method of claim 74, wherein a dose of 0.1-1.0 mg/kg is administered monthly.

76. The method of claim 2, wherein the antibody is administered subcutaneously.

77. The method of claim 76, wherein the antibody is administered at a frequency between weekly and monthly.

78. The method of claim 76, wherein the antibody is administered weekly or biweekly.

79. The method of claim 76, wherein the antibody is administered at a dose of between about 0.01 to about 0.35 mg/kg.

80. The method of claim 76, wherein the antibody is administered at a dose of between about 0.05 to about 0.25 mg/kg.

81. The method of claim 76, wherein the antibody is administered at a dose of between about 0.015 to about 0.2 mg/kg weekly to biweekly.

82. The method of claim 76, wherein the antibody is administered at a dose of between about 0.05 to about 0.15 mg/kg weekly to biweekly.

83. The method of claim 76, wherein the antibody is administered at a dose of between about 0.05 to about 0.07 mg/kg weekly.

84. The method of claim 76, wherein the antibody is administered at a dose of 0.06 mg/kg weekly.

85. The method of claim 76, wherein the antibody is administered at a dose of between about 0.1 to about 0.15 mg/kg biweekly.

86. The method of claim 2, wherein the average serum concentration of the antibody is maintained for at least six months.

87. The method of claim 2, wherein the average serum concentration of the antibody is maintained for at least one year.

88. The method of claim 2, further comprising measuring the concentration of antibody in the serum and adjusting the regime if the measured concentration falls outside the range.

89. The method of claim 2, wherein the antibody is administered subcutaneously at a dose of between about 0.01 to about 0.6 mg/kg and a frequency of between weekly and monthly.

90. The method of claim 2, wherein the antibody is administered at a dose of between about 0.05 to about 0.5 mg/kg.

91. The method of claim 89, wherein the antibody is administered at a dose of between about 0.05 to about 0.25 mg/kg.

92. The method of claim 89, wherein the antibody is administered at a dose of between about 0.015 to about 0.2 mg/kg weekly to biweekly.

93. The method of claim 89, wherein the antibody is administered at a dose of between about 0.05 to about 0.15 mg/kg weekly to biweekly.

94. The method of claim 89, wherein the antibody is administered at a dose of between about 0.05 and about 0.07 mg/kg weekly.

95. The method of claim 89, wherein the antibody is administered at a dose of 0.06 mg/kg weekly.

96. The method of claim 89, wherein the antibody is administered at a dose of between about 0.1 to about 0.15 mg/kg biweekly.

97. The method of claim 89, wherein the antibody is administered at a dose of between about 0.1 to about 0.3 mg/kg monthly.

98. The method of claim 89, wherein the antibody is administered at a dose of 0.2 mg/kg monthly.

99. The method of claim 2, wherein the antibody is administered at a dose of between about 1 to about 40 mg and a frequency of between weekly and monthly.

100. The method of claim 99, wherein the antibody is administered at a dose of between about 5 to about 25 mg.

101. The method of claim 99, wherein the antibody is administered at a dose of between about 2.5 to about 15 mg.

102. The method of claim 99, wherein the antibody is administered at a dose of between about 1 to about 12 mg weekly to biweekly.

103. The method of claim 99, wherein the antibody is administered at a dose of between about 2.5 to about 10 mg weekly to biweekly.

104. The method of claim 99, wherein the antibody is administered at a dose of between about 2.5 to about 5 mg weekly.

105. The method of claim 99, wherein the antibody is administered at a dose of between about 4 to about 5 mg weekly.

106. The method of claim 98, wherein the antibody is administered at a dose of between about 7 to about 10 mg biweekly.

30. A method of effecting prophylaxis against CAA, comprising administering to a patient susceptible to CAA an effective regime of an agent, wherein the agent is an antibody that is specific for the N-terminus of Aβ

or induces such an antibody after administration to the patient and thereby effecting prophylaxis of the patient.

31. Use of an agent, wherein the agent is an antibody that is specific for the N-terminus of Aβ

or induces such an antibody after administration to the patient, in the treatment or prophylaxis of Alzheimer'"'"'s disease.

32. A method of reducing vascular amyloid in a patient, comprising administering an antibody that is specific for the N-terminus of Aβ

in a treatment regime associated with efficacious vascular amyloid removal and reduced incidence of cerebral microhemorrhage.

33. The method of claim 32, further comprising monitoring the patient for cerebral microhemorrhage by MRI.

34. The method of claim 32, further comprising

monitoring the patient for vascular amyloid removal by PET scan.

35. The method of claim 32, wherein the treatment regime is a chronic treatment regime.

36. The method of claim 32, wherein the treatment regime comprises an antibody dosage between 0.01 and 5 mg/kg body weight of the patient and administered weekly to quarterly.

37. The method of claim 36, wherein the dosage of the antibody is 0.1 to 5 mg/kg.

38. The method of claim 36, wherein the dosage is about 0.5 mg/kg.

39. The method of claim 36, wherein the dosage is about 1.5 mg/kg.

40. The method of claim 36, wherein the dosage is between about 0.5 to about 3 mg/kg.

41. The method of claim 36, wherein the dosage is between about 0.5 to about 1.5 mg/kg.

42. The method of claim 36, wherein the dosage is administered every 13 weeks.

43. The method of claim 32, wherein the antibody is administered intravenously or subcutaneously.

44. The method of claim 32, wherein the antibody binds within residues 1-5 of Aβ

.

45. The method of claim 32, wherein the antibody is a humanized, human, or chimeric antibody.

46. The method of claim 45, wherein the antibody is humanized 3D6 or humanized 12A 11.

47. The method of claim 46, wherein the humanized antibody is bapineuzumab.

48. A method of treating Alzheimer'"'"'s disease, comprising administering an antibody that is specific for the N-terminus of Aβ

at a dose that reduces or inhibits development of vascular amyloidogenic pathology, minimizes microhemorrhage, and or reduces or inhibits development of Aβ

plaques.

49. The method of claim 48, wherein the antibody binds within residues 1-5 of Aβ

.

50. The method of claim 48, wherein the antibody is a humanized, human, or chimeric antibody.

51. The method of claim 50, wherein the antibody is humanized 3D6 or humanized 12A 11.

52. The method of claim 51, wherein the humanized antibody is bapineuzumab.

63. The method of any of claims 48-62, wherein the reduction or inhibition of vascular amyloidogenic pathology is a prevention of accumulation of vascular Aβ

or clearance of vascular AD.

53. A method of treating Alzheimer'"'"'s disease, comprising administering an antibody that is specific for the N-terminus of Aβ

at a dose that reduces or inhibits development of vascular amyloidogenic pathology, minimizes microhemorrhage, and or reduces or inhibits development of neuritic pathology.

54. The method of claim 53, wherein the antibody binds within residues 1-5 of Aβ

.

55. The method of claim 53, wherein the antibody is a humanized, human, or chimeric antibody.

56. The method of claim 55, wherein the antibody is humanized 3D6 or humanized 12A11.

57. The method of claim 56, wherein the humanized antibody is bapineuzumab.

58. A method of treating Alzheimer'"'"'s disease, comprising administering an antibody that is specific for the N-terminus of Aβ

at a dose that reduces or inhibits vascular amyloidogenic pathology, minimizes microhemorrhage, and or improves patient'"'"'s cognitive function.

59. The method of claim 58, wherein the antibody binds within residues 1-5 of Aβ

.

60. The method of claim 58, wherein the antibody is a humanized, human, or chimeric antibody.

61. The method of claim 60, wherein the antibody is humanized 3D6 or humanized 12A11.

62. The method of claim 61, wherein the humanized antibody is bapineuzumab.

64. A kit for treatment of CAA, comprising:

a. a glass vial containing a formulation; and

b. instructions to monitor a patient to whom the formulation is administered for CAA.

65. A kit for treatment of CAA, comprising:

a. a glass vial containing a formulation comprising about 0.5 to 3 mg/kg of a humanized anti-Aβ

antibody; and

b. instructions to monitor a patient to whom the formulation is administered for CAA comprising;

i. monitoring the patient for cerebral microhemorrhage by MRI, or

ii. monitoring the patient for vascular amyloid removal by PET scan.

66. A kit for treatment of CAA, comprising:

a. a glass vial containing a formulation comprising;

i. between about 10 mg to about 250 mg of a humanized anti-Aβ

antibody,

ii. about 4% mannitol or about 150 mM NaCl,

iii. about 5 mM to about 10 mM histidine, and

iv. about 10 mM methionine; and

b. instructions to monitor a patient to whom the formulation is administered for CAA comprising;

i. monitoring the patient for cerebral microhemorrhage by MRI, or

ii. monitoring the patient for vascular amyloid removal by PET scan.

67. A kit for treatment of Alzheimer'"'"'s disease, comprising:

a. a glass vial containing a formulation comprising;

i. between about 10 mg to about 250 mg of a humanized anti-Aβ

antibody,

ii. about 4% mannitol or about 150 mM NaCl,

iii. about 5 mM to about 10 mM histidine, and

iv. about 10 mM methionine; and

b. instructions to monitor a patient to whom the formulation is administered for Alzheimer'"'"'s disease comprising;

i. monitoring the patient for cerebral microhemorrhage by MRI, or

ii. monitoring the patient for vascular amyloid removal by PET scan.

68. A kit for treatment of CAA and Alzheimer'"'"'s disease, comprising:

a. a glass vial containing a formulation comprising;

i. between about 10 mg to about 250 mg of a humanized anti-Aβ

antibody,

ii. about 4% mannitol or about 150 mM NaCl,

iii. about 5 mM to about 10 mM histidine, and

iv. about 10 mM methionine; and

b. instructions to monitor a patient to whom the formulation is administered for CAA and Alzheimer'"'"'s disease comprising;

i. monitoring the patient for cerebral microhemorrhage by MRI, or

ii. monitoring the patient for vascular amyloid removal by PET scan.